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Although increasing research is focusing on age-related comorbidities (ARC) among people living with HIV (PLHIV), no studies have concomitantly assessed non-HIV age-related neurological disorders (e.g., Alzheimer’s dementia). A total of 254 PLHIV and 69 HIV-negative controls completed baseline medical history and cognitive testing. ARC data were collected from medical records over the subsequent 9-10 years and included all types of strokes, all types of dementia, mild cognitive impairment, Parkinson's disease, motor neuron disease (grouped into a non-HIV age-related neurological category), cardiovascular disease, chronic kidney disease, chronic liver disease, chronic lung disease, non-AIDS cancers, osteoporosis, and diabetes. Kaplan–Meier curves assessed differences in the incident rates (per 1000 person year) of groups of ARC as defined above and combined ARC (i.e., development of any of the ARC) among younger (baseline age < 50) and older (baseline age ≥ 50) PLHIV and younger and older controls. Cox-proportional hazard models assessed the individual and interaction effects of HIV status and chronological age, in addition to a range of demographic and clinical variables including historical and baseline HIV brain involvement on the risk of developing combined ARC. Older PLHIV had a higher incidence of cardiovascular disease, osteoporosis, and combined ARC compared to other groups (p < 0.05). Incident rate of non-HIV age-related neurological disorders was 2.3 [0.93, 4.79] per 1000 person year. While this incident rate was higher in older PLHIV (5.37 [1.97, 11.92]) than older HIV-negative participants (3.58 [0.18-17.67]), this was not significant. In multivariate analyses, HIV status and chronological age, but not their interaction, and smoking were associated with higher risk of combined ARC (p < 0.05). In analyses focusing on PLHIV, older age and taking abacavir/efavirenz/atazanavir/darunavir containing antiretroviral treatments at the time of diagnosis were associated with greater ARC (p < 0.05). Non-HIV age-related neurological disorders are uncommon in older PLHIV, where the majority were < 70 years of age at the end of follow-up. However, the greater burden of ARC among older PLHIV, most of which are established dementia risk factors, warrants the establishment of commensurate prevention strategies and greater attention to neurocognitive screening.

Background As people living with HIV now have a life expectancy approaching that of the general population, clinical care focuses increasingly on the management and prevention of comorbidities and conditions associated with aging. We aimed to assess the prevalence of physical function (PF) limitation among gay and bisexual men (GBM) and determine whether HIV is associated with severe PF limitation in this population. Methods We analysed cross-sectional data from GBM aged ≥55 years in the Australian Positive and Peers Longevity Evaluation Study who completed a self-administered survey on health and lifestyle factors. PF was measured using the Medical Outcomes Study–Physical Functioning scale. Factors associated with severe PF limitation were assessed using logistic regression. Results The survey was completed by 381 men: 186 without HIV and 195 with HIV. Median age was 64.3 years for GBM without HIV and 62.1 years for GBM with HIV. Compared with men without HIV, those with HIV had higher proportions of severe (13.3% vs 8.1%) and moderate-to-severe (26.7% vs 24.2%) PF limitation. Severe PF limitation commonly involved difficulty with vigorous activity (95% with severe PF limitation described being limited a lot), climbing several flights of stairs (68.4% limited a lot), bending, kneeling or stooping (60.5% limited a lot), and walking 1 km (55.0% limited a lot). In a model adjusted for age, body mass index, typical duration of physical activity, psychological distress, and number of comorbidities, we found a significant association between HIV and severe PF limitation (adjusted odds ratio 3.3 vs not having HIV, 95% confidence interval 1.3–8.7). Conclusions The biological mechanisms underlying this association require further investigation, particularly given the growing age of the HIV population and inevitable increase in the burden of PF limitation.

Treatment inertia is a recognised barrier to blood pressure control, and simpler, more effective treatment strategies are needed. We hypothesised that a hypertension management strategy starting with a single pill containing ultra-low-dose quadruple combination therapy would be more effective than a strategy of starting with monotherapy.QUARTET was a multicentre, double-blind, parallel-group, randomised, phase 3 trial among Australian adults (≥18 years) with hypertension, who were untreated or receiving monotherapy. Participants were randomly assigned to either treatment, that started with the quadpill (containing irbesartan at 37·5 mg, amlodipine at 1·25 mg, indapamide at 0·625 mg, and bisoprolol at 2·5 mg) or an indistinguishable monotherapy control (irbesartan 150 mg). If blood pressure was not at target, additional medications could be added in both groups, starting with amlodipine at 5 mg. Participants were randomly assigned using an online central randomisation service. There was a 1:1 allocation, stratified by site. Allocation was masked to all participants and study team members (including investigators and those assessing outcomes) except the manufacturer of the investigational product and one unmasked statistician. The primary outcome was difference in unattended office systolic blood pressure at 12 weeks. Secondary outcomes included blood pressure control (standard office blood pressure140/90 mm Hg), safety, and tolerability. A subgroup continued randomly assigned allocation to 12 months to assess long-term effects. Analyses were per intention to treat. This trial was prospectively registered with the Australian New Zealand Clinical Trials Registry, ACTRN12616001144404, and is now complete.From June 8, 2017, to Aug 31, 2020, 591 participants were recruited, with 743 assessed for eligibility, 152 ineligible or declined, 300 participants randomly assigned to intervention of initial quadpill treatment, and 291 to control of initial standard dose monotherapy treatment. The mean age of the 591 participants was 59 years (SD 12); 356 (60%) were male and 235 (40%) were female; 483 (82%) were White, 70 (12%) were Asian, and 38 (6%) reported as other ethnicity; and baseline mean unattended office blood pressure was 141 mm Hg (SD 13)/85 mm Hg (SD 10). By 12 weeks, 44 (15%) of 300 participants had additional blood pressure medications in the intervention group compared with 115 (40%) of 291 participants in the control group. Systolic blood pressure was lower by 6·9 mm Hg (95% CI 4·9-8·9; p0·0001) and blood pressure control rates were higher in the intervention group (76%) versus control group (58%; relative risk [RR] 1·30, 95% CI 1·15-1·47; p0·0001). There was no difference in adverse event-related treatment withdrawals at 12 weeks (intervention 4·0% vs control 2·4%; p=0·27). Among the 417 patients who continued, uptitration occurred more frequently among control participants than intervention participants (p0·0001). However, at 52 weeks mean unattended systolic blood pressure remained lower by 7·7 mm Hg (95% CI 5·2-10·3) and blood pressure control rates higher in the intervention group (81%) versus control group (62%; RR 1·32, 95% CI 1·16-1·50). In all randomly assigned participants up to 12 weeks, there were seven (3%) serious adverse events in the intervention group and three (1%) serious adverse events in the control group.A strategy with early treatment of a fixed-dose quadruple quarter-dose combination achieved and maintained greater blood pressure lowering compared with the common strategy of starting monotherapy. This trial demonstrated the efficacy, tolerability, and simplicity of a quadpill-based strategy.National Health and Medical Research Council, Australia.

BACKGROUND HIV preexposure prophylaxis (PrEP) with fixed-dose tenofovir disoproxil fumarate (TDF) and emtricitabine has been associated with low rates of renal impairment in clinical trials. Large-scale PrEP implementation may result in higher rates, as the prevalence of associated risk factors may be higher than in trial populations. METHODS A posthoc analysis of EPIC-NSW, a large Australian multicentre PrEP implementation trial for patients at high risk of HIV infection. Participants were eligible for inclusion if they commenced PrEP between 1 March 2016 and 30 April 2018, and had renal function assessed at baseline and at least once more before the censor date. The primary outcome was new-onset renal impairment, defined as an estimated glomerular filtration rate (eGFR)

People with human immunodeficiency virus (HIV) have higher rates of certain comorbidities, particularly cardiovascular disease and cancer, than people without HIV1–5. In view of observations that somatic mutations associated with age-related clonal hematopoiesis (CH) are linked to similar comorbidities in the general population6–10, we hypothesized that CH may be more prevalent in people with HIV. To address this issue, we established a prospective cohort study, the ARCHIVE study (NCT04641013), in which 220 HIV-positive and 226 HIV-negative participants aged 55 years or older were recruited in Australia. Demographic characteristics, clinical data and peripheral blood were collected to assess the presence of CH mutations and to identify potential risk factors for and clinical sequelae of CH. In total, 135 CH mutations were identified in 100 (22.4%) of 446 participants. CH was more prevalent in HIV-positive participants than in HIV-negative participants (28.2% versus 16.8%, P = 0.004), overall and across all age groups; the adjusted odds ratio for having CH in those with HIV was 2.16 (95% confidence interval 1.34–3.48, P = 0.002). The most common genes mutated overall were DNMT3A (47.4%), TET2 (20.0%) and ASXL1 (13.3%). CH and HIV infection were independently associated with increases in blood parameters and biomarkers associated with inflammation. These data suggest a selective advantage for the emergence of CH in the context of chronic infection and inflammation related to HIV infection. In a prospective cohort study, HIV-positive participants have a higher incidence of clonal hematopoiesis than HIV-negative ones, implicating clonal hematopoiesis in the increased risks of individuals with HIV for malignancy and cardiovascular disease.

SUMMARY Co-formulated tenofovir disoproxil plus emtricitabine is highly effective as pre-exposure prophylaxis for HIV It is suitable for men who have sex with men, for heterosexual sex and for people who use intravenous drugs when there is a risk of HIV infection Pre-exposure prophylaxis is one pill per day and can be prescribed by all medical practitioners and nurse practitioners via the Pharmaceutical Benefits Scheme. It is best prescribed in a three-monthly program with regular monitoring for patient adherence, safety, HIV and other sexually transmitted infections Prophylaxis is well tolerated but requires monitoring for kidney toxicity and low bone density

As people living with HIV now have a life expectancy approaching that of the general population, clinical care focuses increasingly on the management and prevention of comorbidities and conditions associated with aging. We aimed to assess the prevalence of physical function (PF) limitation among gay and bisexual men (GBM) and determine whether HIV is associated with severe PF limitation in this population.We analysed cross-sectional data from GBM aged ≥55years in the Australian Positive and Peers Longevity Evaluation Study who completed a self-administered survey on health and lifestyle factors. PF was measured using the Medical Outcomes Study-Physical Functioning scale. Factors associated with severe PF limitation were assessed using logistic regression.The survey was completed by 381 men: 186 without HIV and 195 with HIV. Median age was 64.3years for GBM without HIV and 62.1years for GBM with HIV. Compared with men without HIV, those with HIV had higher proportions of severe (13.3% vs 8.1%) and moderate-to-severe (26.7% vs 24.2%) PF limitation. Severe PF limitation commonly involved difficulty with vigorous activity (95% with severe PF limitation described being limited a lot), climbing several flights of stairs (68.4% limited a lot), bending, kneeling or stooping (60.5% limited a lot), and walking 1km (55.0% limited a lot). In a model adjusted for age, body mass index, typical duration of physical activity, psychological distress, and number of comorbidities, we found a significant association between HIV and severe PF limitation (adjusted odds ratio 3.3 vs not having HIV, 95% confidence interval 1.3-8.7).The biological mechanisms underlying this association require further investigation, particularly given the growing age of the HIV population and inevitable increase in the burden of PF limitation.

Objectives Evidence of premature cognitive ageing amongst people living with HIV (PLHIV) remains controversial due to previous research limitations including underpowered studies, samples with suboptimal antiretroviral access, varying rate of virological control, high rate of AIDS, over‐representation of non‐community samples, and inclusion of inappropriate controls. The current study addresses these limitations, while also considering mental health and non‐HIV comorbidity burden to determine whether PLHIV showed premature cognitive ageing compared with closely comparable HIV‐negative controls. Methods This study enrolled 254 PLHIV [92% on antiretroviral therapy; 84% with HIV RNA

Objective(s) To evaluate changes in injecting and sexual risk behaviours, and hepatitis C virus (HCV) reinfection incidence among people with HIV/HCV coinfection following unrestricted access to direct-acting antiviral therapy in Australia. Design Prospective observational cohort study (2014-2018). Methods Among people enrolled in the Control and Elimination of HCV from HIV-infected individuals within Australia study, changes in injecting and sexual behaviour were evaluated, including injecting drug use (IDU) in the last 6 months and last month, frequency of IDU and equipment sharing, condom-less anal intercourse with casual male partner(s), and group sex. HCV reinfection incidence was evaluated with follow-up through May 2018. Results Overall, 272 HIV/HCV antibody-positive participants [median age; 50 years, 96% male, 83% identified as gay and bisexual men (GBM)] had behavioural data at enrolment and follow-up (median 2.91 years) available for analysis. The proportion reporting IDU in the last 6 months remained stable from enrolment (35%) to follow-up (39%). Among GBM, the proportion reporting condom-less anal intercourse with casual partner(s) at enrolment (48%) and follow-up (46%) was also similar. Reinfection was detected in five individuals (all GBM) during total follow-up of 474 person-years for an overall incidence of 1.05 per 100 person-years (95% confidence interval, 0.44-2.53). Conclusion No change was observed in levels of injecting or sexual risk behaviour for HCV infection following unrestricted access to direct-acting antiviral therapy in an Australian HIV/HCV cohort. Incidence of HCV reinfection was low potentially reflecting high levels of treatment coverage within this population. Continued screening and rapid retreatment of reinfection will be required to maintain progress towards elimination.

Background People living with HIV (PLHIV) are at increased risk of atherosclerotic cardiovascular disease (ASCVD) and prone to statin-related adverse events from drug-drug interactions with certain antiretroviral regimens. Objectives This study sought to evaluate the efficacy and safety of evolocumab in dyslipidemic PLHIV. Methods BEIJERINCK is a randomized, double-blind, multinational trial comparing monthly subcutaneous evolocumab 420 mg with placebo in PLHIV with hypercholesterolemia/mixed dyslipidemia taking maximally-tolerated statin therapy. The primary endpoint was the percent change (baseline to week 24) in low-density lipoprotein cholesterol (LDL-C); secondary endpoints included achievement of LDL-C Results A total of 464 patients were analyzed (mean age of 56.4 years, 82.5% male, mean duration with HIV of 17.4 years). ASCVD was documented in 35.6% of patients, and statin intolerance/contraindications to statin use were present in 20.7% of patients. Evolocumab reduced LDL-C by 56.9% (95% CI: 61.6%, 52.3%) from baseline to week 24 versus placebo. An LDL-C level of Conclusions Evolocumab was safe and significantly reduced lipid levels in dyslipidemic PLHIV on maximally-tolerated statin therapy. Evolocumab is an effective therapy for lowering atherogenic lipoproteins in PLHIV with high cardiovascular risk.

People with HIV (PWH) are at an increased risk of atherosclerotic cardiovascular disease. Suboptimal responses to statin therapy in PWH may result from antiretroviral therapies (ARTs). This open-label extension study aimed to evaluate the long-term safety and efficacy of evolocumab up to 52 weeks in PWH.This final analysis of a multinational, placebo-controlled, double-blind, randomized phase 3 trial evaluated the effect of monthly subcutaneous evolocumab 420 mg on low-density lipoprotein cholesterol (LDL-C) during the open-label period (OLP) following 24 weeks of double-blind period in PWH with hypercholesterolemia/mixed dyslipidemia. All participants enrolled had elevated LDL-C or nonhigh-density lipoprotein cholesterol (non-HDL-C) and were on stable maximally tolerated statin and stable ART.Efficacy was assessed by percentage change from baseline in LDL-C, triglycerides, and atherogenic lipoproteins. Treatment-emergent adverse events (TEAEs) were examined.Of the 467 participants randomized in the double-blind period, 451 (96.6%) received at least one dose of evolocumab during the OLP (mean age of 56.4 years, 82.5% male, mean duration with HIV of 17.4 years). By the end of the 52-week OLP, the overall mean (SD) percentage change in LDL-C from baseline was -57.8% (22.8%). Evolocumab also reduced triglycerides, atherogenic lipid parameters (non-HDL-C, apolipoprotein B, total cholesterol, very-low-density lipoprotein cholesterol, and lipoprotein[a]), and increased HDL-C. TEAEs were similar between placebo and evolocumab during the OLP.Long-term administration of evolocumab lowered LDL-C and non-HDL-C, allowing more PWH to achieve recommended lipid goals with no serious adverse events.NCT02833844.http://links.lww.com/QAD/C441.

Background Limited data exist that compare clinical outcomes of 2-drug regimens (2DRs) and 3-drug regimens (3DRs) in people living with human immunodeficiency virus. Methods Antiretroviral treatment–experienced individuals in the International Cohort Consortium of Infectious Diseases (RESPOND) who switched to a new 2DR or 3DR from 1 January 2012–1 October 2018 were included. The incidence of clinical events (AIDS, non-AIDS cancer, cardiovascular disease, end-stage liver and renal disease, death) was compared between regimens using Poisson regression. Results Of 9791 individuals included, 1088 (11.1%) started 2DRs and 8703 (88.9%) started 3DRs. The most common 2DRs were dolutegravir plus lamivudine (22.8%) and raltegravir plus boosted darunavir (19.8%); the most common 3DR was dolutegravir plus 2 nucleoside reverse transcriptase inhibitors (46.9%). Individuals on 2DRs were older (median, 52.6 years [interquartile range, 46.7–59.0] vs 47.7 [39.7–54.3]), and a higher proportion had ≥1 comorbidity (81.6% vs 73.9%). There were 619 events during 27 159 person-years of follow-up (PYFU): 540 (incidence rate [IR] 22.5/1000 PYFU; 95% confidence interval [CI]: 20.7–24.5) on 3DRs and 79 (30.9/1000 PYFU; 95% CI: 24.8–38.5) on 2DRs. The most common events were death (7.5/1000 PYFU; 95% CI: 6.5–8.6) and non-AIDS cancer (5.8/1000 PYFU; 95% CI: 4.9–6.8). After adjustment for baseline demographic and clinical characteristics, there was a similar incidence of events on both regimen types (2DRs vs 3DRs IR ratio, 0.92; 95% CI: .72–1.19; P = .53). Conclusions This is the first large, international cohort to assess clinical outcomes on 2DRs. After accounting for baseline characteristics, there was a similar incidence of events on 2DRs and 3DRs. 2DRs appear to be a viable treatment option with regard to clinical outcomes. Further research on resistance barriers and long-term durability of 2DRs is needed.

People with human immunodeficiency virus (HIV) have higher rates of certain comorbidities, particularly cardiovascular disease and cancer, than people without HIV

Summary Background Daily pre-exposure prophylaxis (PrEP) is effective in preventing HIV, but few long-term data are available on effectiveness and adherence in real-world settings. Here, we report trends in HIV incidence over 3 years in individuals at high risk who were prescribed PrEP in New South Wales (NSW), as well as adherence before the transition to subsidised PrEP. Methods Expanded PrEP Implementation in Communities–New South Wales (EPIC-NSW) was a pragmatic, prospective, single-arm, implementation study of daily, oral PrEP in 31 sites (sexual health clinics, general practices, and a hospital) in NSW, Australia. Eligible participants were HIV-negative adults (aged ≥18 years) who were at high risk of HIV infection as defined in local PrEP guidelines. Participants were prescribed coformulated (once-daily, oral tablet) tenofovir disoproxil fumarate (300 mg) and emtricitabine (200 mg) as HIV PrEP and were followed up with HIV testing, sexually transmitted infection testing, and PrEP dispensing. Originally planned for 3700 participants followed for 1 year, the study was expanded so that all eligible participants in the state could obtain PrEP and extended until publicly subsidised PrEP became available in Australia. The primary outcome was new HIV infection among all participants who were dispensed PrEP at least once and had at least one follow-up HIV test result. Adherence was estimated by medication possession ratio (MPR), defined as the proportion of PrEP pills dispensed in 90 days, assuming daily dosing. This study is registered with ClinicalTrials.gov , NCT02870790 . Findings Between March 1, 2016, and April 30, 2018, we enrolled 9709 participants. 9596 participants were dispensed PrEP, of whom 9448 (98·3%) were gay or bisexual men. Participants were followed up until March 31, 2019, with at least one follow-up HIV test available in 9520 (99·2%) participants. Mean MPR declined from 0·93 to 0·64 from the first to the ninth quarter. There were 30 HIV seroconversions over 18 628 person-years, an incidence of 1·61 per 1000 person-years (95% CI 1·13–2·30). Being younger, living in a postcode with fewer gay men, reporting more risk behaviours at baseline, and having an MPR of less than 0·6 were each univariately associated with increased HIV incidence. In the final year of follow-up, when PrEP was mostly purchased rather than provided free by the study, HIV incidence remained low at 2·24 per 1000 person-years (1·46–3·44). Interpretation HIV incidence remained low over up to 3 years of follow-up, including during a transition from study-provided to publicly subsidised PrEP. In a setting of affordable PrEP and associated health-care services, very low HIV incidence of 1 to 2 per 1000 person-years can be maintained in gay and bisexual men who were previously at high risk. Funding New South Wales Ministry of Health, Australian Capital Territory Health Directorate, Gilead Sciences.

Objectives This paper aims to address the concerns around ongoing immune activation, inflammation, and resistance in those ageing with HIV that represent current challenges for clinicians. Methods Presentations at a symposium addressing issues of ageing with HIV infection were reviewed and synthesised. Results The changing natural history and demographics of human immunodeficiency virus (HIV)-infected individuals means new challenges in contemporary management. In the early years of the epidemic,management was focussed on acute, potentially life-threatening AIDS-related complications. From initial monotherapy with first-generation antiretroviral therapy (ART), the development of combination highly active ART (HAART) allowed HIV control but ART toxicities, treatment adherence and drug resistance emerged as major issues. Today, the availability of potent and tolerable ART has made viral suppression achievable in most people living with HIV (PLHIV), and clinicians are confronted with managing a chronic condition among an ageing population. The combination of diseases of ageing and the co-morbidities associated with HIV-infection, even when well controlled, results in a complex set of challenges for many older PLHIV. There is a growing appreciation that many non-AIDS-related co-morbidities are caused, at least in part, by persistent, low-grade immune activation, inflammation, and hypercoagulability, despite suppressive ART. Conclusions In order to further improve HIV management, it is important to understand the enduring effects of chronically suppressed HIV infection, the potential contribution of these factors to the ageing process, the possibility of drug resistance, and the impact of different treatment strategies, including early ART initiation.

Integrase strand transfer inhibitor-based antiretroviral therapy can cause weight gain. It is unknown if this is a class effect, with limited data regarding raltegravir. In 37 virologically suppressed adults (36 men, mean age 49 years) who switched from tenofovir disoproxil fumarate to raltegravir 400 mg twice daily, mean weight changes from baseline at weeks 24, 48 and 96 were not significant (maximum 0.8 kg at week 24; all P ≥ 0.16). Weight gain may not occur with all integrase strand transfer inhibitors.

Objectives: As HIV-positive people age, diagnosis and management of comorbidities associated with ageing are of increasing concern. In this study, we aimed to compare the self-reported prevalences of heart disease, stroke, thrombosis and diabetes in older Australian HIV-positive and HIV-negative gay and bisexual men (GBM). Methods: We analysed data from the Australian Positive & Peers Longevity Evaluation Study (APPLES), a study of a prospectively recruited cross-sectional sample of 228 (51.1%) HIV-positive and 218 (48.9%) HIV-negative GBM, aged >= 55 years. Regression methods were used to assess the association of HIV status with self-reported comorbidities. Results: Of 446 patients, 389 [200 (51.4%) HIV-positive] reported their disease history. The reported prevalence of comorbidities was higher in the HIV-positive group than in the HIV-negative group: heart disease, 19.5 versus 12.2%; stroke, 7.5 versus 4.2%; thrombosis, 10.5 versus 4.2%; and diabetes, 15.0 versus 9.0%, respectively. In adjusted analyses, HIV-positive GBM had significantly increased odds of reporting heart disease [adjusted odds ratio (aOR) 1.99; P = 0.03] and thrombosis (aOR 2.87; P = 0.01). In our analysis, HIV status was not significantly associated with either age at diagnosis of heart disease (median 53 years for HIV-positive GBM versus 55 years for HIV-negative GBM; P = 0.64) or 5-year cardiovascular disease (CVD) risk estimated using the Framingham risk score. Conclusions: HIV-positive GBM more commonly reported heart disease and thrombosis compared with their HIV-negative peers. These results further highlight the need to understand the impact of HIV on age-related comorbidities in GBM, to guide optimal screening and treatment strategies to reduce the risk of these comorbidities among the HIV-positive population.

Summary Background HIV pre-exposure prophylaxis (PrEP) is highly effective in men who have sex with men (MSM) at the individual level, but data on population-level impact are lacking. We examined whether rapid, targeted, and high-coverage roll-out of PrEP in an MSM epidemic would reduce HIV incidence in the cohort prescribed PrEP and state-wide in Australia's most populous state, New South Wales. Methods The Expanded PrEP Implementation in Communities–New South Wales (EPIC-NSW) study is an implementation cohort study of daily co-formulated tenofovir disoproxil fumarate and emtricitabine as HIV PrEP. We recruited high-risk gay men in a New South Wales-wide network of 21 clinics. We report protocol-specified co-primary outcomes at 12 months after recruitment of the first 3700 participants: within-cohort HIV incidence; and change in population HIV diagnoses in New South Wales between the 12-month periods before and after PrEP roll-out. The study is registered with ClinicalTrials.gov , number NCT02870790 . Findings We recruited 3700 participants in the 8 months between March 1, 2016, and Oct 31, 2016. 3676 (99%) were men, 3534 (96%) identified as gay, and 149 (4%) as bisexual. Median age was 36 years (IQR 30–45 years). Overall, 3069 (83%) participants attended a visit at 12 months or later. Over 4100 person-years, two men became infected with HIV (incidence 0·048 per 100 person-years, 95% CI 0·012–0·195). Both had been non-adherent to PrEP. HIV diagnoses in MSM in New South Wales declined from 295 in the 12 months before PrEP roll-out to 221 in the 12 months after (relative risk reduction [RRR] 25·1%, 95% CI 10·5–37·4). There was a decline both in recent HIV infections (from 149 to 102, RRR 31·5%, 95% CI 11·3 to 47·3) and in other HIV diagnoses (from 146 to 119, RRR 18·5%, 95% CI −4·5 to 36·6). Interpretation PrEP implementation was associated with a rapid decline in HIV diagnoses in the state of New South Wales, which was greatest for recent infections. As part of a combination prevention approach, rapid, targeted, high-coverage PrEP implementation is effective to reduce new HIV infections at the population level. Funding New South Wales Ministry of Health, Gilead Sciences.

PrELUDE study evaluated daily pre-exposure prophylaxis (PrEP) in high-risk individuals in Australia. This open-label, single-arm study tested participants for HIV/STI and collected behavioural information three-monthly. We report trends over 18 months in medication adherence, side-effects, HIV/STI incidence and behaviour. 320 gay/bisexual men (GBM), 4 women and 3 transgender participants, followed on average 461 days, reported taking seven pills/week on 1,591 (88.5%) occasions and 4-6 pills/week on 153 (8.5%) occasions. No HIV infections were observed. STI incidence was high and stable, while gonorrhoea infections declined from 100.0 to 25.8/100 person-years between 6 and 15 months (p

Supplemental Digital Content is Available in the Text., Background: Raltegravir 1200mg (2×600mg tablets) once daily (QD) demonstrated noninferior efficacy and similar safety to raltegravir 400mg twice daily (BID) at week 48 of the ONCEMRK trial. Here, we report the week 96 results from this study. Methods: ONCEMRK is a phase 3, multicenter, double-blind, noninferiority trial comparing raltegravir 1200mg QD with raltegravir 400mg BID in treatment-naive HIV-1–infected adults. Participants were assigned (2:1) to raltegravir 2×600mg QD or 400mg BID, both with emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) for 96 weeks. Randomization was stratified by screening HIV-1 RNA and hepatitis B/C status. Efficacy was assessed as the proportion of participants with HIV-1 RNA 260 cells/mm3 from baseline in both groups. Resistance to raltegravir was infrequent, occurring in 0.8% of each treatment group through week 96. Adverse event rates were similar for the 2 regimens. Conclusions: In HIV-1–infected treatment-naive adults receiving FTC/TDF, raltegravir 1200mg QD demonstrated noninferior efficacy to raltegravir 400mg BID that was durable to week 96, with a safety profile similar to raltegravir 400mg BID.

Aim: Evaluate the efficacy of flurbiprofen 8.75 mg spray for sore throat relief. Patients & methods: Randomized, double-blind study in adults with sore throat due to upper respiratory tract infection who took flurbiprofen (n = 249) or placebo spray (n = 256). Pain relief was assessed using the Sore Throat Relief Rating Scale. Results: Flurbiprofen spray provided significantly greater relief versus placebo from 20 min to 6 h (p < 0.0001; maximum difference: 75 min). Sore throat severity was reduced ≥-2.2 on the Sore Throat Scale from 75 min to 6 h, indicating meaningful relief. Significantly more patients taking flurbiprofen spray reported ≥30 min of ‘at least moderate’ relief versus placebo over 6 h (p < 0.0001). Most adverse events were mild. Conclusion: Flurbiprofen spray provides rapid, long-lasting and clinically meaningful relief from sore throat (ANZCTR: ACTRN12612000457842).

HIV-1-infected, virologically suppressed adults wanting to simplify or change their non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens may benefit from switching to the single-tablet regimen of elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (E/C/F/TDF).We examined differences in the proportion of participants with HIV-1 RNA 50 copies/mL (Snapshot analysis), change in CD4 cell count, safety, and patient-reported outcomes in participants switching to E/C/F/TDF from an NNRTI + FTC/TDF (TVD) regimen.STRATEGY-NNRTI was a 96-week, phase 3b, randomized, open-label, study examining the efficacy, safety, and tolerability of switching to E/C/F/TDF in virologically suppressed individuals (HIV-1 RNA 50 copies/mL) on an NNRTI + TVD regimen. Participants were randomized to switch or remain on their NNRTI-based regimen (no-switch).At Week 96, 87% (251/290) of switch and 80% (115/143) of no-switch participants maintained HIV-1 RNA 50 copies/mL (difference 6.1%; 95% CI -1.3 to 14.2%; p = 0.12) according to the FDA-defined snapshot algorithm. Both groups had similar proportions of subjects with virologic failure (2.8% switch, 1.4% no-switch). Discontinuations resulting from adverse events were infrequent (3% [9/291] switch, 2% [3/143] no-switch). Three switch participants (1%) discontinued due to renal adverse events (2 of the 3 before Week 48). Switch participants reported significant improvements in neuropsychiatric symptoms by as early as Week 4, and which were maintained through Week 96.E/C/F/TDF is safe and effective and reduces NNRTI-associated neuropsychiatric symptoms for virologically suppressed HIV-positive adults switching from an NNRTI plus FTC/TDF-based regimen.

Screening tools to identify HIV-associated neurocognitive disorder (HAND) are primarily devised to detect cognitive impairment on a single occasion. With the chronicity of HIV infection and the risk of HAND developing or progressing despite viral control, it may be pertinent to repeat HAND screening at more than one time point. Despite this, there are limited data on longitudinal use of such screening tools, particularly with regard to the role of practice effects. Additionally, no guidelines currently exist on the timeframe between testing intervals, or recommendation of the magnitude of baseline impairment that warrants follow-up testing. The aim of the current paper was to review existing evidence for longitudinal validity of HAND screening tools. Only those HAND screening tools previously found to have high cross-sectional criterion validity were included. Preliminary recommendations for clinical use and future research are proposed including in international settings.

Objective To compare the performance of four reliable change (RC) methods with respect to measuring cognitive change on the Cogstate Computerized Battery (CCB). Method We assessed cognitive change in 57 healthy, urban, well-educated males on the CCB at baseline and 6 months (Median age = 50, 65% university-educated). The study CCB version comprised seven measures covering attention, processing speed, verbal learning, and memory. Raw scores were z-score transformed using age-corrected Cogstate norms (CN) or the sample mean and standard deviation (internal standardization [IS]), and then averaged to create composite z-scores. Composite scores were entered into four RC formulae. RC was defined based on a 90% two-tailed confidence interval. Change scores were compared as continuous (z-scores) and ordinal variables (RC outcomes). Results CCB composite score reliability (rXY = .78–.79) was replicated in an age- and sex-matched Cogstate database sample of similar size. There was good overall agreement between the four RC methods (Bland–Altman Mdiff = .00; 95% limits of agreement with the mean—CN: z = ± .90; IS: z = ± .93), with each model adhering closely to the 10% rate of RC expected by chance alone (largest χ2 = .86, p = .99). Initial norming strategy (CN or IS) did not affect these outcomes. Conclusions Norming strategy and RC method choice did not significantly impact cognitive change predictions on CCB composite scores. A series of example case data are provided to practically demonstrate the steps involved in applying the longitudinal norms generated in this study. Research in more diverse normative samples is warranted.

Background Microelimination of hepatitis C virus (HCV) among people living with human immunodeficiency virus (HIV) may be feasible in Australia, given unrestricted access to direct-acting antiviral (DAA) therapy from 2016. Our aim was to evaluate progress towards elimination goals within HIV/HCV-coinfected adults in Australia following universal DAA access. Methods The CEASE prospective cohort study enrolled adults with HIV/HCV, irrespective of viremic status, from 14 primary and tertiary clinics in Australia. Annual and cumulative HCV treatment uptake, outcome, and HCV RNA prevalence were evaluated, with follow-up through May 2018 (median follow-up, 2.63 years). Factors associated with DAA uptake were analyzed. Results Between July 2014 and March 2017, 402 participants who were HIV/HCV antibody positive were enrolled (95% male [80% gay and bisexual men,], 13% cirrhosis, 80% history of injecting drug use [39% currently injecting]). Following universal DAA access, annual HCV treatment uptake in those eligible increased from 7% and 11% per year in 2014 and 2015, respectively, to 80% in 2016. By 2018, cumulative HCV treatment uptake in those ever eligible for treatment was 91% (336/371). HCV viremic prevalence declined from 82% (95% CI, 78–86%) in 2014 to 8% (95% CI, 6–12%) in 2018. Reinfection was reported in only 5 participants for a reinfection incidence of 0.81 per 100 person-years (95% CI, 0.34–1.94). Conclusions High uptake and effectiveness of unrestricted DAA therapy in Australia have permitted rapid treatment scale-up, with a dramatic reduction in HCV infection burden and low reinfection rate among people living with HIV, suggesting that microelimination is feasible. Clinical Trials Registration NCT02102451.

Summary Background Effective two-drug regimens could decrease long-term drug exposure and toxicity with HIV-1 antiretroviral therapy (ART). We therefore aimed to evaluate the efficacy and safety of a two-drug regimen compared with a three-drug regimen for the treatment of HIV-1 infection in ART-naive adults. Methods We conducted two identically designed, multicentre, double-blind, randomised, non-inferiority, phase 3 trials: GEMINI-1 and GEMINI-2. Both studies were done at 192 centres in 21 countries. We included participants (≥18 years) with HIV-1 infection and a screening HIV-1 RNA of 500 000 copies per mL or less, and who were naive to ART. We randomly assigned participants (1:1) to receive a once-daily two-drug regimen of dolutegravir (50 mg) plus lamivudine (300 mg) or a once-daily three-drug regimen of dolutegravir (50 mg) plus tenofovir disoproxil fumarate (300 mg) and emtricitabine (200 mg). Both drug regimens were administered orally. We masked participants and investigators to treatment assignment: dolutegravir was administered as single-entity tablets (similar to its commercial formulation, except with a different film colour), and lamivudine tablets and tenofovir disoproxil fumarate and emtricitabine tablets were over-encapsulated to visually match each other. Primary endpoint was the proportion of participants with HIV-1 RNA of less than 50 copies per mL at week 48 in the intention-to-treat-exposed population, using the Snapshot algorithm and a non-inferiority margin of −10%. Safety analyses were done on the safety population. GEMINI-1 and GEMINI-2 are registered with ClinicalTrials.gov, numbers NCT02831673 and NCT02831764, respectively. Findings Between July 18, 2016, and March 31, 2017, 1441 participants across both studies were randomly assigned to receive either the two-drug regimen (n=719) or three-drug regimen (n=722). At week 48 in the GEMINI-1 intention-to-treat-exposed population, 320 (90%) of 356 participants receiving the two-drug regimen and 332 (93%) of 358 receiving the three-drug regimen achieved plasma HIV-1 RNA of less than 50 copies per mL (adjusted treatment difference −2·6%, 95% CI −6·7 to 1·5); in GEMINI-2, 335 (93%) of 360 in the two-drug regimen and 337 (94%) of 359 in the three-drug regimen achieved HIV-1 RNA of less than 50 copies per mL (adjusted treatment difference −0·7%, 95% CI −4·3 to 2·9), showing non-inferiority at a −10% margin in both studies (pooled analysis: 655 [91%] of 716 in the two-drug regimen vs 669 [93%] of 717 in the three-drug regimen; adjusted treatment difference −1·7%, 95% CI −4·4 to 1·1). Numerically, more drug-related adverse events occurred with the three-drug regimen than with the two-drug regimen (169 [24%] of 717 vs 126 [18%] of 716); few participants discontinued because of adverse events (16 [2%] in the three-drug regimen and 15 [2%] in the two-drug regimen). Two deaths were reported in the two-drug regimen group of GEMINI-2, but neither was considered to be related to the study medication. Interpretation The non-inferior efficacy and similar tolerability profile of dolutegravir plus lamivudine to a guideline-recommended three-drug regimen at 48 weeks in ART-naive adults supports its use as initial therapy for patients with HIV-1 infection. Funding ViiV Healthcare.

Summary Background Evidence on viral load and HIV transmission risk in HIV-serodiscordant male homosexual couples is limited to one published study. We calculated transmission rates in couples reporting condomless anal intercourse (CLAI), when HIV-positive partners were virally suppressed, and daily pre-exposure prophylaxis (PrEP) was not used by HIV-negative partners. Methods In the Opposites Attract observational cohort study, serodiscordant male homosexual couples were recruited from 13 clinics in Australia, one in Brazil, and one in Thailand. At study visits, HIV-negative partners provided information on sexual behaviour and were tested for HIV and sexually transmitted infections; HIV-positive partners had HIV viral load tests, CD4 cell count, and sexually transmitted infection tests done. Viral suppression was defined as less than 200 copies per mL. Linked within-couple HIV transmissions were identified with phylogenetic analysis. Incidence was calculated per couple-year of follow-up, focusing on periods with CLAI, no use of daily PrEP, and viral suppression. One-sided upper 95% CI limits for HIV transmission rates were calculated with exact Poisson methods. Findings From May 8, 2012, to March 31, 2016, in Australia, and May 7, 2014, to March 31, 2016, in Brazil and Thailand, 358 couples were enrolled. 343 couples had at least one follow-up visit and were followed up for 588·4 couple-years. 258 (75%) of 343 HIV-positive partners had viral loads consistently less than 200 copies per mL and 115 (34%) of 343 HIV-negative partners used daily PrEP during follow-up. 253 (74%) of 343 couples reported within-couple CLAI during follow-up, with a total of 16 800 CLAI acts. Three new HIV infections occurred but none were phylogenetically linked. There were 232·2 couple-years of follow-up and 12 447 CLAI acts in periods when CLAI was reported, HIV-positive partners were virally suppressed, and HIV-negative partners did not use daily PrEP, resulting in an upper CI limit of 1·59 per 100 couple-years of follow-up for transmission rate. Interpretation HIV treatment as prevention is effective in men who have sex with men. Increasing HIV testing and linking to immediate treatment is an important strategy in HIV prevention in homosexual men. Funding National Health and Medical Research Council; amfAR, The Foundation for AIDS Research; ViiV Healthcare; and Gilead Sciences.

Hepatitis C virus (HCV) infection is a leading cause of morbidity and mortality in patients with HIV-1. The C-EDGE CO-INFECTION study assessed the efficacy, safety, and tolerability of grazoprevir (MK-5172) plus elbasvir (MK-8742) in patients with HCV and HIV co-infection.In this uncontrolled, non-randomised, phase 3, open-label, single-arm study, treatment-naive patients with chronic HCV genotype 1, 4, or 6 infection and HIV co-infection, with or without cirrhosis, were enrolled from 37 centres in nine countries across Europe, the USA, and Australia. Patients were either naive to treatment with any antiretroviral therapy (ART) or stable on ART for at least 8 weeks. All patients received grazoprevir 100 mg plus elbasvir 50 mg in a fixed-dose combination tablet once daily for 12 weeks. The primary endpoint was sustained virological response (HCV RNA15 IU/mL) 12 weeks after the end of therapy (SVR12). The primary population for efficacy analyses was all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, number NCT02105662.Between June 11, 2014, and Aug 29, 2014, 218 patients were enrolled and received grazoprevir plus elbasvir for 12 weeks, all of whom completed follow-up at week 12. SVR12 was achieved by 210 (96%) of 218 patients (95% CI 92·9-98·4). One patient did not achieve SVR12 because of a non-virological reason, and seven patients without cirrhosis relapsed (two subsequently confirmed as reinfections). All 35 patients with cirrhosis achieved SVR12. The most common adverse events were fatigue (29; 13%), headache (27; 12%), and nausea (20; 9%). No patient discontinued treatment because of an adverse event. Two patients receiving ART had transient HIV viraemia.This HCV treatment regimen seems to be effective and well tolerated for patients co-infected with HIV with or without cirrhosis. These data are consistent with previous trials of this regimen in the monoinfected population. This regimen continues to be studied in phase 3 trials.Merck SharpDohme Corp.

Summary Background Once daily regimens are preferred for HIV-1 treatment, to facilitate adherence and improve quality of life. We compared a new once daily formulation of raltegravir to the currently marketed twice daily formulation. Methods In this randomised, double-blind, parallel-group, phase 3, non-inferiority study, we enrolled participants aged 18 years or older with HIV-1 RNA of 1000 or more copies per mL and no previous antiretroviral treatment at 139 sites worldwide. We randomly assigned participants (2:1) via an interactive voice and web response system to raltegravir 1200 mg (two 600 mg tablets) orally once daily or raltegravir 400 mg (one tablet) orally twice daily, each with tenofovir disoproxil fumarate and emtricitabine orally once daily, for up to 96 weeks. A computer-generated allocation schedule stratified randomisation by screening HIV-1 RNA value and co-infection with hepatitis B or C. Participants, sponsor personnel, investigators, and study site personnel involved in the treatment or evaluation of the participants were unaware of the treatment group assignments. The primary endpoint was the proportion of participants with HIV-1 RNA less than 40 copies per mL at week 48 assessed with the US Food and Drug Administration Snapshot algorithm. Non-inferiority was concluded if the lower bound of the two-sided 95% CI was greater than −10%. We assessed efficacy and safety in all participants who received one dose or more of study treatment. This study is registered with ClinicalTrials.gov, number NCT02131233. Findings Between May 26, 2014, and Dec 5, 2014, 802 participants were enrolled and randomly assigned, 533 to once daily treatment and 269 to twice daily; 797 received study therapy, 531 once daily and 266 twice daily. At week 48, 472 (89%) of 531 once daily recipients and 235 (88%) of 266 twice daily recipients achieved HIV-1 RNA less than 40 copies per mL (treatment difference 0·5%, 95% CI −4·2 to 5·2). Drug-related adverse events occurred in 130 (24%) of 531 participants in the once daily group (one of which was serious; none led to treatment discontinuation) and 68 (26%) of 266 participants in the twice daily group (two of which were serious; two led to treatment discontinuation). The most common drug-related adverse events were nausea (39 [7%] vs 18 [7%]), headache (16 [3%] vs 12 [5%]), and dizziness (12 [2%] vs eight [3%]). No treatment-related deaths were reported. Interpretation A once daily raltegravir 1200 mg regimen was non-inferior compared with raltegravir 400 mg twice daily for initial treatment of HIV-1 infection. These results support the use of raltegravir 1200 mg once daily for first-line therapy. Funding Merck & Co, Inc.

The most common reasons for switching HIV-1 therapy in patients with virologic suppression are treatment regimen simplification and resolving tolerability issues. Single-pill regimens that include an integrase inhibitor are recommended options. A retrospective clinical audit was performed to determine the motivations for switching to dolutegravir (DTG)/abacavir (ABC)/lamivudine (3TC) at high HIV-caseload general practice clinics in Australia. The most common reasons for switching from a prior suppressive therapy to DTG/ABC/3TC were simplification of regimen, resolving toxicity/intolerance and patient preference (73%, 13% and 12%, respectively). Kaplan–Meier analysis showed that the probability of patients remaining on DTG/ABC/3TC therapy at 12 months was 95.1%. Switching to DTG/ABC/3TC from a range of other regimens was associated with a discontinuation rate of 3.2%, with 2.5% of patients discontinuing due to adverse events and no patients discontinuing due to virologic failure. Switching to DTG/ABC/3TC was a viable treatment strategy in this cohort of Australian patients.